EP4001260B1 - Dérivé de dibromobenzyle, stéréoisomère ou sel de celui-ci, et son procédé de préparation et son utilisation - Google Patents

Dérivé de dibromobenzyle, stéréoisomère ou sel de celui-ci, et son procédé de préparation et son utilisation

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Publication number
EP4001260B1
EP4001260B1 EP20842969.6A EP20842969A EP4001260B1 EP 4001260 B1 EP4001260 B1 EP 4001260B1 EP 20842969 A EP20842969 A EP 20842969A EP 4001260 B1 EP4001260 B1 EP 4001260B1
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EP
European Patent Office
Prior art keywords
dibromobenzyl
amino
derivative
stereoisomer
adamantane
Prior art date
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EP20842969.6A
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German (de)
English (en)
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EP4001260A1 (fr
EP4001260A4 (fr
EP4001260C0 (fr
Inventor
Guodong Cen
Maoting YANG
Shaojun TAN
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Chengdu Shibeikang Biomedical Technology Co Ltd
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Chengdu Shibeikang Biomedical Technology Co Ltd
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, in particular to a dibromobenzyl derivative, a stereoisomer or a pharmaceutically acceptable salt thereof, and a preparation method and an application of the dibromobenzyl derivative.
  • ambroxol effectively improves the ventilation function and relieving dyspnea by promoting the secretion of pulmonary surfactant and airway surface liquid, breaking down the mucopolysaccharide-protein fiber in phlegm, promoting the mucolysis, significantly reducing the viscosity of phlegm, enhancing the bronchial mucociliary transport and promoting the phlegm discharge.
  • the ambroxol has become a commonly used apophlegmatic drug with apophlegmatic effect, toxicity and resistance significantly improved from the bromhexine.
  • ambroxol was used clinically in the form of hydrochloride and applicable to acute/chronic pulmonary diseases with abnormal phlegm secretion and poor expectoration function, such as expectorant treatment of acute exacerbation of chronic bronchitis, asthmatic bronchitis and bronchial asthma, preventive treatment of post-operative pulmonary complications and treatment of infant respiratory distress syndrome (IRDS) in premature infants and newborns.
  • IRDS infant respiratory distress syndrome
  • Document US 3 536 713 A patented on 1970 relates to compounds which are N-(hydroxy-cyclohexyl)-aminobenzylamines useful as antipyretics, secretolytics and antitussives and including the molecule of ambroxol.
  • ambroxol hydrochloride has been marketed in China in the form of lyophilized powder for injection as well as small- and large-volume parenteral injections.
  • a conventional apophlegmatic drug it has been available in the global market for more than 30 years with clinically qualified effectiveness.
  • the hydroxyl group in the cyclohexane combines with the glucuronic acid in human body and further deactivates the ambroxol. Therefore, the ambroxol hydrochloride has poor in-vivo metabolic stability and needs to be administered 2 or 3 times a day, and unsatisfactory expectorant effect is often reported clinically. Therefore, it is urgent to develop a novel apophlegmatic drug with improved effectiveness and in-vivo stability.
  • the objective of the present invention is to provide a dibromobenzyl derivative, a stereoisomer or a pharmaceutically acceptable salt thereof and a preparation method and an application of the dibromobenzyl derivative.
  • the dibromobenzyl derivative and the stereoisomer have good in-vivo pharmacokinetic stability and enhanced drug efficacy by means of structural modification of cyclohexane in ambroxol, and is applicable to preparation of a respiratory drug, in particular a apophlegmatic drug.
  • the A is the five-membered cycloalkane or the adamantane.
  • the A is the five-membered cycloalkane or the adamantane;
  • the B is C1-C5 alkane, the hydroxyl group, the halogen or the halogenated alkane.
  • the B is C1-C5 alkane, the hydroxyl group, the halogen or the halogenated alkane.
  • the structure of the dibromobenzyl derivative or the stereoisomer thereof is selected from any one of the group consisting of:
  • the dibromobenzyl derivative is selected from the group consisting of:
  • the dibromobenzyl derivative is selected from the group consisting of:
  • the pharmaceutically acceptable salt is formed by the dibromobenzyl derivative and an acid.
  • the acid is acetate, bisulfate, ascorbate, benzoate, benzene sulfonate, citrate, fumarate, hydrochloride, hydrobromide, maleate, mesylate, nitrate, oxalate, phosphate, succinate or sulfate.
  • the reducing agent is sodium borohydride or potassium borohydride.
  • the preparation method includes the following steps: add the amino-A-B, the 2-amino-3,5-dibromobenzaldehyde and 100 mL of tetrahydrofuran to a reaction flask, run overnight reaction by refluxing until the APIs basically disappear, cool to a room temperature, add the sodium borohydride or the potassium borohydride to react for 20-40 hrs, add 200-300 mL of water, extract with 300 mL of ethyl acetate, and produce a compound of the dibromobenzyl derivative or the stereoisomer thereof by vacuum concentration; and on this basis, wash the compound obtained with 100 mL of saturated sodium chloride, acidify it with an acid, and produce corresponding compound salt by vacuum concentration.
  • Also provided in the present invention is an application of the dibromobenzyl derivative, the stereoisomer or the pharmaceutically acceptable salt thereof in preparation of a drug for preventing and treating respiratory diseases.
  • This example discloses a preparation method of a compound 1: 3-((2-amino-3,5-dibromobenzyl)amino)adamantane-1-ol, with a structure shown as follows:
  • mice After 30 mins, these mice are sacrificed, and a section of trachea from inferior thyroid cartilage to branch of trachea is cut off and placed in a test tube containing 1 mL of normal saline, shaken and soaked for 30 mins, and then centrifuged for 10 mins (at 3000 r/min) to obtain a supernatant, which is transferred to another tube, shaken well with 0.1 mL of 1M NaOH, and determined by means of a colorimetric method at a wavelength of 546 nm.
  • the compounds in the Examples 1, 3, 5 and 12 groups and a ambroxol hydrochloride group significantly increase the excretory amounts of phenol red from trachea of mice (* p ⁇ 0.05); and compared with the ambroxol hydrochloride group, the compounds in the Examples 1, 3, 5 and 12 groups significantly increase the excretory amounts of phenol red from trachea of mice ( ⁇ P ⁇ 0.05) and are remarkably superior to the ambroxol hydrochloride.
  • the phenol red test is a classical animal-model expectoration test, the phenol red administrated intraperitoneally is partially excreted from the bronchus of mice, and the compounds in the Examples 1, 3, 5 and 12 groups significantly increase the excretory amounts of phenol red from trachea of mice ( ⁇ P ⁇ 0.05) and are remarkably superior to the ambroxol hydrochloride. Therefore, the application of the compounds in respiratory drugs will result in improved efficacy, in particular the apophlegmatic drugs.
  • 0.2 mL of blood samples is respectively collected from jugular veins before and 15.0 min, 30.0 min, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, 8.0 h, 12.0 h and 24.0 h after the administration, and then centrifuged at a high speed (7800 ⁇ g) for 15 min in a tube containing EDTA-K2.
  • the separated plasma is stored at -15 °C ⁇ -35°C.
  • Example 1 As shown in Table 3, test results are obtained by means of HPLC/MS/MS analysis, compartment model fitting for pharmacokinetic behaviors of the test compounds, and calculation of main pharmacokinetic parameters: Table 3 Pharmacokinetic Parameters Group Test sample T1/2 (h) CL (mL/h/kg) MRT (h) AUC AUC0-inf (h*ng/mL) Example 1 group Example 1 compound 3.58 ⁇ 0.45 * 2095 ⁇ 105* 2.58 ⁇ 0.41* 4472 ⁇ 250* Example 3 group Example 3 compound 3.12 ⁇ 0.34* 2860 ⁇ 165* 2.31 ⁇ 0.36* 3650 ⁇ 180* Example 12 group Example 12 compound 3.43 ⁇ 0.35* 2150 ⁇ 145* 2.65 ⁇ 0.42* 4490 ⁇ 240* Ambroxol hydrochloride group Ambroxol hydrochloride 1.98 ⁇ 0.34 6051 ⁇ 270 1.18 ⁇ 0.20 1650 ⁇ 71.9 Compared with the ambroxol hydrochloride group, *P ⁇ 0.05; According to Table 3, the Example 1, Example 3 and Example 12 groups are significantly superior to the ambro

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pulmonology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (12)

  1. Dérivé de dibromobenzyle dont la structure est représentée par la formule I, stéréoisomère ou son sel pharmaceutiquement acceptable, où, A est un cycloalcane à cinq membres, un cycloalcane à sept membres ou un adamantane ; et B est un alcane, un groupe hydroxyle, un halogène ou un alcane halogéné.
  2. Dérivé de dibromobenzyle, stéréoisomère ou son sel pharmaceutiquement acceptable selon la revendication 1, caractérisé en ce que le A est le cycloalcane à cinq membres ou l'adamantane.
  3. Dérivé de dibromobenzyle, stéréoisomère ou son sel pharmaceutiquement acceptable selon la revendication 2, caractérisé en ce que B est un alcane en C1-C5, le groupe hydroxyle, l'halogène ou l'alcane halogéné.
  4. Dérivé de dibromobenzyle, stéréoisomère ou son sel pharmaceutiquement acceptable selon la revendication 1, caractérisé en ce que le dérivé de dibromobenzyle ou son stéréoisomère est choisi parmi l'un quelconque du groupe constitué par :
  5. Dérivé de dibromobenzyle, stéréoisomère ou son sel pharmaceutiquement acceptable selon la revendication 4, caractérisé en ce que le dérivé de dibromobenzyle est choisi dans le groupe constitué par :
    3-((2-amino-3,5-dibromobenzyl)amino)adamantane-1-ol,
    4-((2-amino-3,5-dibromobenzyl)amino)adamantane-1-ol,
    (1R,2R)-2-((2-amino-3,5-dibromobenzyl)amino)-cyclopentanol,
    (2-amino-3,5-dibromobenzyl)-3-méthyl-adamantane-1-amine,
    (1R,2S)-2-trifluorométhyl-((2-amino-3,5-dibromobenzyl)amino)-cyclopentane,
    (2-amino-3,5-dibromobenzyl)-2-fluoro-adamantane-1-amine,
    (1R,3R)-3-((2-amino-3,5-dibromobenzyl)amino)-cyclopentanol,
    1-((2-amino-3,5-dibromobenzyl)amino)adamantane-2-ol et
    (1S,2R)-2-((2-amino-3,5-dibromobenzyl)amino)-cyclopentanol.
  6. Dérivé de dibromobenzyle, stéréoisomère ou son sel pharmaceutiquement acceptable selon la revendication 5, caractérisé en ce que le dérivé de dibromobenzyle est choisi dans le groupe constitué par :
    3-((2-amino-3,5-dibromobenzyl)amino)adamantane-1-ol ;
    4-((2-amino-3,5-dibromobenzyl)amino)adamantane-1-ol ; et
    (1R,2R)-2-((2-amino-3,5-dibromobenzyl)amino)-cyclopentanol.
  7. Dérivé de dibromobenzyle, stéréoisomère ou son sel pharmaceutiquement acceptable selon la revendication 1, caractérisé en ce que le sel pharmaceutiquement acceptable est formé par le dérivé de dibromobenzyle et un acide.
  8. Procédé de préparation du dérivé de dibromobenzyle avec la structure représentée comme formule I selon la revendication 1, caractérisé en ce qu'il comporte les étapes suivantes : permettre à l'amino-A-B de réagir avec du 2-amino-3,5-dibromobenzaldéhyde, et ajouter un agent réducteur pour la réduction une fois la réaction terminée, avec une formule réactionnelle comme illustré ci-dessous :
  9. Procédé de préparation selon la revendication 8, caractérisé en ce que l'agent réducteur est le borohydrure de sodium ou le borohydrure de potassium.
  10. Dérivé de dibromobenzyle, stéréoisomère ou son sel pharmaceutiquement acceptable selon l'une quelconque des revendications 1 à 6 pour son utilisation dans la préparation d'un médicament pour la prévention et le traitement des maladies respiratoires.
  11. Dérivé de dibromobenzyle pour son utilisation selon la revendication 10, dans lequel le médicament est un médicament apophlégmatique.
  12. Composition pharmaceutique, caractérisée en ce qu'elle comprend le dérivé de dibromobenzyle, le stéréoisomère ou son sel pharmaceutiquement acceptable selon l'une quelconque des revendications 1 à 6 et un support pharmaceutiquement acceptable.
EP20842969.6A 2019-07-24 2020-03-25 Dérivé de dibromobenzyle, stéréoisomère ou sel de celui-ci, et son procédé de préparation et son utilisation Active EP4001260B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910671508.7A CN112279774B (zh) 2019-07-24 2019-07-24 二溴苄基衍生物、其立体异构体或其盐及制法和应用
PCT/CN2020/081092 WO2021012698A1 (fr) 2019-07-24 2020-03-25 Dérivé de dibromobenzyle, stéréoisomère ou sel de celui-ci, et son procédé de préparation et son utilisation

Publications (4)

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EP4001260A1 EP4001260A1 (fr) 2022-05-25
EP4001260A4 EP4001260A4 (fr) 2022-10-12
EP4001260B1 true EP4001260B1 (fr) 2025-10-08
EP4001260C0 EP4001260C0 (fr) 2025-10-08

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EP20842969.6A Active EP4001260B1 (fr) 2019-07-24 2020-03-25 Dérivé de dibromobenzyle, stéréoisomère ou sel de celui-ci, et son procédé de préparation et son utilisation

Country Status (6)

Country Link
US (1) US12006276B2 (fr)
EP (1) EP4001260B1 (fr)
JP (1) JP7344607B2 (fr)
CN (1) CN112279774B (fr)
PL (1) PL4001260T3 (fr)
WO (1) WO2021012698A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
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CN114685292A (zh) * 2021-03-17 2022-07-01 成都施贝康生物医药科技有限公司 反式金刚烷氨衍生物或其盐的用途
CN115108923A (zh) * 2021-03-17 2022-09-27 成都施贝康生物医药科技有限公司 反式金刚烷氨衍生物或其盐、及制备方法、组合物和用途
CN115108939A (zh) * 2021-03-17 2022-09-27 成都施贝康生物医药科技有限公司 反式-4-[(2-氨基-3,5-二溴苄基)氨基]-金刚烷-1-醇的中间体及制法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL125434C (fr) * 1961-11-20 1900-01-01
DE1593579B1 (de) 1966-05-10 1972-02-03 Thomae Gmbh Dr K Hydroxy-cyclohexylamine,deren physiologisch vertraeglichen Saeureadditionssalze und Verfahren zu ihrer Herstellung
DE2027944A1 (de) * 1970-06-06 1971-12-16 Knoll Ag, Chemische Fabriken, 6700 Ludwigshafen N-substituierte Norcamphanderivate
AT332375B (de) * 1973-04-13 1976-09-27 Thomae Gmbh Dr K Verfahren zur herstellung von neuen aminobenzylaminen sowie deren saureadditionssalzen
CN101544572B (zh) * 2008-03-26 2013-03-20 连云港恒邦医药科技有限公司 一种氨溴索衍生物及其制备方法
CN103012167A (zh) * 2012-12-16 2013-04-03 石药集团中诺药业（石家庄）有限公司 一种盐酸氨溴索的制备方法
CN105693764B (zh) 2015-11-30 2018-06-26 成都苑东生物制药股份有限公司 一种氨溴索衍生物及应用

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JP7344607B2 (ja) 2023-09-14
US20220251024A1 (en) 2022-08-11
JP2022542675A (ja) 2022-10-06
WO2021012698A1 (fr) 2021-01-28
US12006276B2 (en) 2024-06-11
CN112279774A (zh) 2021-01-29
EP4001260A1 (fr) 2022-05-25
EP4001260A4 (fr) 2022-10-12
PL4001260T3 (pl) 2026-02-09
EP4001260C0 (fr) 2025-10-08
CN112279774B (zh) 2023-05-30

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